Adolescence is a critical period in the maturation of a subcortical-prefrental neural system central to stress regulation and the regulation of hedonically-driven behaviors such as drug use and abuse. Emerging preclinical data support the observation that prenatal and early life stressors constitute an important vulnerability factor associated with dysregulated stress response mechanisms in adolescence and young adulthood. That is, a key mechanism for the initiation of drug use and abuse in adolescence may be a dysregulated balance between reward and stress response systems. Further, there is evidence of a significant association between early trauma history before age 18, recent adverse life events, laboratory- induced acute stress/drug cue reactivity and drug use relapse in addicted women, as compared to men. These findings suggest that the proposed dysfunctional stress-regulation system as one mechanism for initiation of drug use and then abuse in adolescence may be differentially more active in girls compared to boys. We propose to study adolescent response to stressors and gender differences in that response in a well- characterized cohort of adolescent males and females beginning at age 14 who have been studied since birth and who were exposed or non-exposed to cocaine and other drugs prenatally. Both exposed and non- exposed adolescents have grown up in psychosocial adversity with one group also exposed to the early stressors of a drug-using environment. This cohort provides a unique opportunity to examine the relation between early experience and functioning assessed prospective^ and stress response and drug use in adolescence. Two hundred adolescent girls and boys will participate in laboratory based stress-induction sessions with detailed assessments of their behavioral and physiological response. Adolescents will then be followed with biyearly assessments of drug use and other risk taking behaviors. Specifically we aim to examine sex differences in adolescents as well as the impact of early life stressors, especially prenatal exposure to drugs of abuse, in measures of emotion state, HPA activation, physiological arousal and urinary catecholamine response to both a social stress and to stress, appetitive and neutral imagery; to examine the interaction between early life stressors and current adverse life events on adolescent response to social stress and stress imagery and to examine the relation between stress response as measured physiologically and behaviorally and initiation of drug use in a one to four year follow-up period. Understanding possible mechanisms for the initiation of drug use and early abuse, and how these mechanisms work differentially in females and males will inform the development of more effective and targeted interventions in adolescents at risk.